Worldwide, antibiotic resistance is a major contemporary public health threat due to rapid emergence of resistant bacteria and endangering the efficacy of antibiotics. There are significant number of reports on clinical failure of β-lactam and β-lactamase inhibitor combination and even carbapenems due to various carbapenem resistance mechanisms. The increasing rate of the antibiotic resistance and its impact on treatment failure encouraged us to study newly reported concept of antibiotic adjuvant entities (AAEs) by which the increasing failure rate of antibiotics can be controlled. These AAEs have been developed for both Gram-positive and Gram-negative multidrug-resistant (MDR) infections. Elores (ceftriaxone + sulbactam with adjuvant ethylenediaminetetraacetic acid (EDTA)) and Potentox (cefepime + amikacin with adjuvant potassium chloride) are the AAEs for Gram-negative MDR pathogens each catering to a different type of resistance and Vancoplus (ceftriaxone + vancomycin with adjuvant L-arginine), another AAE, can help us to last longer in the war against antibiotic-resistant Gram-positive bugs particularly which cause complicated lower respiratory tract infection (LRTI) leading to pneumonia. These new antibiotic additions (Elores, Potentox, and Vancoplus) to the current armamentarium to treat MDR infections, including pneumonia, can help us combat against antimicrobial resistance more efficiently.
- antibiotic resistance
Pneumonia commonly described as infection of lungs is classified according to where or how it is acquired: community-acquired, healthcare-associated, hospital-acquired, or ventilator-associated pneumonia [1, 2]. According to the area of lung affected, pneumonia can be lobar pneumonia, bronchial pneumonia, and acute interstitial pneumonia . Pneumonia can be bacterial, viral, and less commonly fungal . In the pediatric age group, pneumonia may additionally be classified as non-severe, severe, or very severe depending on the signs and symptoms .
Hospital-acquired pneumonia (HAP) or nosocomial pneumonia refers to any pneumonia contracted by a patient in a hospital at least 48–72 h after being admitted. Community-acquired pneumonia (CAP) is defined as pneumonia acquired outside a hospital or a long-term care facility. It occurs within 48 h of hospital admission or in a patient presenting with pneumonia who does not have any of the characteristics of healthcare-associated pneumonia. The nosocomial pneumonia, which is associated with mechanical ventilation for a duration of more than 48 h, is termed as ventilator-associated pneumonia (VAP), whereas the healthcare-associated pneumonia is defined as the pneumonia occurring in non-hospitalized patients having contact with the healthcare system.
From 1930s, prior to the discovery of antibiotic, till date pneumonia remains the major cause of death among all age groups accounting for four million deaths annually. The rate of death is highest among children aged less than 5 years worldwide . According to a study conducted by Farooqui et al. , 3.6 million (3.3–3.9 million) episodes of severe pneumonia and 0.35 million (0.31–0.40 million) all-cause pneumonia deaths occurred in children younger than 5 years in India. Furthermore, 0.56 million (0.49–0.64 million) severe episodes of pneumococcal pneumonia and 105,000 (92,000–119,000) pneumococcal deaths occurred in India. According to American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA), 2005, HAP had a crude mortality rate of 30–70% with an estimated attributable mortality rate to pneumonia between 27 and 50%. According to some estimates, VAP contributes up to 50–85% of all cases of nosocomial pneumonia [7, 8]. Furthermore, it mainly occurs in intensive care unit (ICU) patients where they most often require ventilator support, amounting to 9–27% of all mechanically ventilated patients . It is estimated that four million cases of CAP occur annually in the United States, of which 20–25% are severe enough to warrant hospitalization . Pneumonia is responsible for about 1.6 million deaths among children aged <5 years in Africa and South-East Asia regions [10, 11]. HAP and VAP are important causes of mortality and morbidity, which continue to baffle the treating physicians in today’s era of MDR.
4. Economic burden
Pneumonia is one of the most common causes of economic burden across the globe involving great exploitation of health resources. World Health Organization (WHO) has indicated that more death of children occurs due to pneumonia than any other diseases. According to a study conducted in India , the average cost per patient not put on ventilator is INR 27,123, whereas the cost associated with ventilated patient is almost twice INR 44,812. Ventilator support is the most expensive intervention adding to the cost of care followed by the cost of antibiotics and investigations and still making the patient more prone to complicated infections like biofilm. Thus, the disease adds significantly to the cost of hospital care and to the length of hospital stay. The situation does not seem to improve as antibiotic pipeline is virtually dry and the resistance appears to be further mounting in most parts of the world as per the latest Center for Disease Dynamics, Economics and Policy (CDDEP) reports.
The etiology of pneumonia in high-income countries is different than in low-income countries [12, 13]. It has been reported that viruses contribute to 30–67% cases of CAP in developed countries and are more frequently identified in children aged less than 1 year than in those aged above 2 years . Bacteria are more frequently identified with increasing age, resulting in mixed infections being less common with age .
Respiratory syncytial virus (RSV) is the prime cause of viral pneumonia in children admitted to hospital in developing countries, followed by influenza A and B, parainfluenza, human metapneumovirus, and adenovirus . The bacterial pathogens causing pneumonia include
The outline for the diagnosis of pneumonia is highlighted in WHO/UNICEF Integrated Management of Childhood Illness (IMCI) guidelines. Fever and cough are the most common ones. Fever is present in 65–90% and cough in 75–96% of patients with pneumonia. Other typical respiratory complaints include sputum production, dyspnea, and chest pain . In a hospital, there are numerous investigations available including radiography and microbiological methods to investigate pneumonia.
The treatment of pneumonia depends on the age, the severity of illness, the likely causative agents, and their resistance patterns. Guidelines recommended the use of third- and fourth-generation cephalosporins, BL + BLI (β-lactam + β-lactamase inhibitor) combinations, and even carbapenems for the management of Gram-negative infections and vancomycin/linezolid for the management of Gram-positive infections.
8. Antibiotic resistance
Worldwide, antibiotic resistance is a major contemporary public health threat due to rapid emergence of resistant bacteria and endangering the efficacy of antibiotics . In 2014, the WHO warned that the antibiotic resistance crisis is becoming extremely serious  and is attributed to the overuse and misuse of these medications, as well as a lack of new drug development by the pharmaceutical industry . Different molecular mechanisms are responsible for the development of antimicrobial resistance such as alteration of bacterial cell permeability, acquisition of extended spectrum β-lactamase production (ESBLs), and metallo-β-lactamases (MBLs), bacterial biofilm formation, activation of efflux pump, bacterial conjugation, and curli fiber formation [17, 20–25].
In India, the prevalence of ESBL producing organisms among Gram-negative pathogens was up to 73.5% . Similarly, the prevalence of MBLs is also increasing at an immense rate [27, 28]. Scores of reports highlighting antibiotic resistance because of efflux pump in bacteria is increasing significantly . Outer membrane permeability and β-lactamase are key factor for the resistance of bacteria to antibiotics . The increasing rate of the biofilm problem and its impact on antibiotic resistance triggered us to think new means which could disrupt the biofilm formation by inhibiting bacterial adhesion and curli formation.
There are significant number of reports on the clinical failure of β-lactam and β-lactamase inhibitor combination and even carbapenems due to various carbapenem resistance mechanisms. A number of studies have demonstrated the decreased susceptibility of Enterobacteriaceae to cephalosporins and other drugs [31, 32]. The ESBLs enzyme confers resistance not only to broad-spectrum cephalosporins, including oxymino-β-lactam antibiotics, but also to other commonly used antibiotics, including aminoglycosides and quinolone [33, 34]. Overexpression of efflux pump is often associated with extrusion of most of the β-lactam antibiotics, leading to decreased susceptibility of antibiotics .
A decreased susceptibility rates of
In view of the above background, the increasing rate of the antibiotic resistance and its impact on treatment failure encouraged us to study newly reported concept of antibiotic adjuvant entity by which the increasing failure rate of antibiotics can be controlled. Adjuvants are commonly used chemical entities which do not possess antibacterial activity of their own but help antibiotic in breaking one or more mechanisms of resistance and accelerate antibiotic effectiveness making AAEs as empiric choice . Information regarding the prevalence of antimicrobial resistance in pathogens can be used for selecting an optional treatment. Earlier studies have supported the combination therapy of two or more drugs in combination with adjuvant (which are usually non-antibiotic in nature) as a suitable approach to reduce the frequency of antibiotic resistance .
A few of such synergistic novel antimicrobial adjuvant entities, their mechanisms, and clinical outcomes, which can revolutionize the future, will be discussed in this book chapter. These AAEs have been developed for both Gram-positive and Gram-negative multidrug-resistant infections. Elores (ceftriaxone + sulbactam with adjuvant EDTA) and Potentox (cefepime + amikacin with adjuvant potassium chloride (KCl)) are the AAEs for Gram-negative MDR pathogens each catering to a different type of resistance, and Vancoplus (ceftriaxone + vancomycin with adjuvant L-arginine), another AAE, can help us to last longer in the war against antibiotic-resistant Gram-positive bugs particularly which cause complicated LRTI leading to pneumonia (HAP/CAP/VAP/HCAP).
8.1. CSE1034 (Elores)
CSE1034 is a novel combination of third-generation cephalosporin “ceftriaxone,” an irreversible β-lactamase inhibitor “sulbactam,” and non-antibiotic adjuvant Antibiotic Resistance Breaker (ARB) “disodium edetate.” Due to synergistic action of the inhibition of cell wall by ceftriaxone accompanied by the specific inhibition of β-lactamases by β-lactam component produced by common Gram-negative and Gram-positive pathogens, this drug has been reported to be affective against multiple types of MDR organisms. CSE1034 has proven activity against a wide range of ESBL and MBL producing Gram-negative pathogens and is used as a treatment option for a multitude of bacterial infections.
8.1.1. Mechanism of action
Ceftriaxone acts by binding to penicillin-binding proteins (PBPs) which are transpeptidases that catalyze the cross-linking of the peptidoglycan polymers synthesizing cell wall and subsequently inhibiting bacterial cell wall synthesis. The cell wall of bacteria consists of pentapeptide units attached to a polysaccharide backbone with alternating units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). PBPs act on a terminal d-alanyl-d-alanine moiety on a pentapeptide unit and catalyze the formation of a peptide bond between the penultimate D-alanine and a glycine unit on an adjacent peptidoglycan strand. The ceftriaxone structure is the mimic of D-alanyl-D-alanine moiety and the PBPs wrongly attack the β-lactam ring in ceftriaxone, which leads to the inactivation of PBPs. As the peptidoglycan synthesis is essential to maintain bacterial cell wall integrity, so the inhibition of PBPs leads to damage and destruction of the cell wall and ultimately in cell lysis.
Sulbactam is a potent, highly specific inhibitor of a wide variety of β-lactamases including penicillinases and cephalosporinases produced commonly by different strains of bacteria and chromosomally mediated enzymes induced in some strains of
Disodium edetate is a non-antibiotic adjuvant acts as ARB which chelates the divalent metal ions particularly zinc that functions as a cofactor for carbapenemases. As zinc is necessary for the MBL activity, thus EDTA activity makes MBL-producing organisms susceptible toward Elores [24, 25, 42, 43]. Disodium edetate also chelates divalent metal ions located in the outer membrane causing destabilization of outer membrane and thus resulting in enhanced penetration of drugs inside the bacterial cells. Moreover, CSE1034 downregulates acrA, acrB, tolC, mexA, and mexB genes in MexA-MexB-OprM efflux pump, which in turn enhances the susceptibility of Gram-negative bacteria (GNB) toward CSE1034 which overexpress this efflux transporter.
8.1.2. Activity spectrum
Elores has a broad spectrum of activity against both Gram-positive and Gram-negative bacteria pathogens. It is reported to be active against both ESBL and MBL producing organisms, including
With regard to Potentox for pneumonia, first of all, let’s see what this unique AAE offers. Potentox is a synergistic antibiotic combination of cefepime and amikacin and potassium chloride. Cefepime is the fourth-generation broad-spectrum cephalosporin. It is frequently used as first-line empirical therapy for healthcare-associated infections, including those caused by suspected Gram-negative bacteria. Cefepime has relatively low propensity for degradation by ESBLs compared to other cephalosporins. Cefepime also remains active against infections due to AmpC-producing organisms. Amikacin is one of the most commonly used aminoglycosides and it has the highest recommendation from IDSA 2016 for usage in nosocomial pneumonia cases as an empirical antibiotic in the combination protocol against nosocomial pneumonia. Potentox (cefepime + amikacin) is not just the most active combination in vitro [23, 49] but also has demonstrated efficacy in vivo as the most active combination [50, 51].
8.2.1. Mechanism of action
Amikacin, which belongs to aminoglycoside antibiotic group, blocks the production of protein by binding irreversibly to the four nucleotides of 16S rRNA of 30S ribosomal subunit of the pathogenic organism. This region where amikacin binds is known to interact with the wobble base in the anti-codon of tRNA. Thus, amikacin interferes with the tRNA acceptor site and prevents the formation of initiation complex with messenger RNA. This leads to misreading of mRNA so incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides and the breakup of polysomes into nonfunctional monosomes.
Cefepime, a fourth-generation cephalosporin, is bactericidal and has the same mode of action as other β-lactam antibiotics. It disrupts the synthesis of the peptidoglycan layer of bacterial cell wall which is important for cell wall structural integrity.
Potassium chloride is a metal halide salt composed of potassium and chloride that is used as an adjuvant in Potentox. Interestingly, Potentox due to adjuvant potassium chloride exhibits activity against Quinolone-resistant Gram-negative pathogens, the prevalence of which is rising alarmingly in developing countries.
8.2.2. Activity spectrum
Both cefepime and amikacin individually have become a victim of high level of resistance . This is where precisely, Potentox is used in combating these multidrug-resistant pathogens as Potentox has demonstrated in vitro and in vivo activity against these resistant isolates to which cefepime and amikacin are resistant individually. Global surveillance studies demonstrate that the actual acquired fluoroquinolone resistance rates are highly variable and are as high as almost 100%, particularly in Asia, whereas resistance rates in Europe and North America range from <10% in rural areas to >30% which is still pretty high. This highlights the importance of Potentox use to target multiple drug resistance effectively which developed both in community and in hospital settings.
Multi-centric randomized comparative open-labeled phase 3 trial of synergistic antibiotic combination of cefepime and amikacin versus cefepime alone was conducted in nosocomial pneumonia and showed superiority of Potentox in efficacy over cefepime alone.
Potentox and Elores can serve as a true carbapenem sparer as medically important Gram-negative bacteria are developing resistance very fast against this valuable class of antibiotic. In the era of antimicrobial resistance, the judicious use of different antimicrobials in a balanced fashion can help us in preserving these antibiotics for longer duration.
While we look for HAP/VAP due to Gram-positive bacteria, methicillin-resistant
Vancoplus is a novel AAE of ceftriaxone and vancomycin along with l-arginine as adjuvant caters to all types of mixed infection especially MRSA, VRSA, VISA, and hGISA .
8.3.1. Mechanism of action
The vancomycin plays its bactericidal role primarily through inhibiting cell wall biosynthesis. Specifically, vancomycin forms hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the N-acetylmuramic acid- and N-acetylglucosamine-peptide subunits and thus prevents their incorporation into the peptidoglycan matrix, a major component of Gram-positive cell walls. Additionally, vancomycin is known to alter bacterial-cell-membrane permeability and RNA synthesis. No cross-resistance is known to occur between vancomycin and other antibiotics. The mechanism of action of ceftriaxone is already discussed in Elores drug section.
8.3.2. Activity spectrum
Earlier, the natural glycopeptide vancomycin was considered the drug of choice to treat MRSA infections. However, the concerns regarding the efficacy of vancomycin against MRSA including poor bactericidal activity and high recurrence rates are increasing . Stevens and Moise Broder have reported in two studies, published in CID 2004 and 2006, respectively, that MRSA treatment failure rate is associated with higher vancomycin minimum inhibitory concentration (MIC). Higher vancomycin MIC is associated with higher mortality in HAP/VAP due to MRSA. We have started witnessing vancomycin resistance, either in the intermediate range or in the full-resistance range, even in India. Among high-risk MRSA bacteremia patients, Sakoulas et al.  documented treatment failure rates of 44% when vancomycin MICs were <0.5 μg/ml and of 90% when vancomycin MICs were 1–2 μg/ml (
European Antimicrobial Resistance Surveillance Network (EARS-Net) data show that the occurrence of methicillin-resistant
Additionally, one of the biggest challenges in the management of
In a nut shell, a number of agencies (Infectious Diseases Society of America/American Thoracic Society, US FDA and SWAB, Asia Pacific Society for Critical Care Medicines, European Society of Intensive Care Medicines, Indian Society of Critical Care Medicines, etc.) have issued guidelines for the treatment of CAP/HAP/HCAP, CUTI/sepsis and the management of other critical ICU infections. The concept of antibiotic adjuvant entity is new and will take time to be a part of these guidelines. The author has tried to share the latest and emerging trends in MDR infection management with proven efficacy and safety in millions of patients across various developing economies. The world has now started talking about adjuvant therapy and soon these therapies will be part of standard critical infection management program. These new antibiotic additions (Elores, Potentox, and Vancoplus) to the current armamentarium to treat MDR infections including pneumonia can help us combat against antimicrobial resistance more efficiently due to presence of ARB as adjuvant.
8.4. Adjuvant therapy to treat secondary bacterial superinfections caused by influenza and other respiratory viruses
Viral influenza is very common in community and is often mistreated with antibiotics. Antibacterial drugs are not meant for viral infections and misuse leads to creation of resistant bacterial species. Viral-bacterial co-infections in humans are well documented. Viral infections often lead to bacterial superinfections. Bacterial superinfections accompanied by influenza and other respiratory virus infections contribute to the significant morbidity and mortality particularly among elderly and young children.
Bacterial infection could be concomitant with influenza viral infection as a result of an enhanced pneumonic illness or may happen soon following influenza virus has been widely cleared from the lungs, when the host seems to be more susceptible to bacterial infection [57, 58].
Morbidity and mortality have been recognized to be greater in cases of influenza-associated bacterial infection in all age groups . The increase in influenza infection during winter is often associated with a rise in cases of community-acquired pneumonia. The most common causes of CAP are
The mechanisms of superinfection are very complex process. Several reports indicate that changes due to virus in the respiratory tract prime the upper airway and lung make way for subsequent bacterial infection. Super bacterial infections are accompanied by virus-induced cytopathology, leading to immunological impairment, which could be caused in part by the overproduction of inflammatory cytokines . Transformation of the immune response by curtailing the capacity of the host to clear bacteria may contribute to the severity of the resulting infection . Earlier studies on animal model have demonstrated that influenza predisposes to bacterial pneumonia [63, 65, 66]. It has been reported with 7–21 days of lag time for the onset of bacterial infection following seasonal influenza. However, shorter times from onset to death have been noticed in pandemic periods [67–69].
8.5. Antibiotic adjuvants potentiate anti-inflammatory properties of antibiotics
There is limited information on the effectiveness of adjuvant therapy for the treatment of bacterial complications of influenza. In a very recent study , explored the adjuvant effect of polyactin (PA), an inactivated trivalent influenza virus (ITIV) with or without PA or MF59 was instilled intranasally once a week in BALB/c mice. Results showed that PA is a novel mucosal adjuvant for intranasal vaccination with the inactivated trivalent influenza vaccine that has safe and effective mucosal adjuvanticity in mice and successfully induces both serum and mucosal antibody responses and a cell-mediated response.
The inflammatory response of viral infections results in the excessive production of reactive oxygen species (ROS) in the cells and tissues, and antioxidant system cannot neutralize them. Imbalance in this protective mechanism can lead to the damage of cellular molecules such as DNA, proteins, and lipids . Moreover, the role of ROS in inflammation has been investigated vigorously by earlier authors [72, 73]. ROS are thought to be key signaling molecules in the progression of inflammatory disorders. It induces inflammation by the induction of COX-2, inflammatory cytokines (TNFα, interleukin 1 (IL-1), and IL-6), chemokines (IL-8 and CXCR4), and pro-inflammatory transcription factors (NF-κB) . Inflammatory cytokines trigger inflammation, causing the immune response to weaken which may help to increase the risk of bacterial infection. This rise in inflammatory markers with infection is a cascade reaction and is not easily broken only by antibiotics. Adjuvants have a major role to play here. Buret  reported that some antibiotics, such as the 16-membered macrolide tilmicosin, may generate anti-inflammatory benefits by modulating the production of pro-inflammatory mediators, and by inducing neutrophil apoptosis. Many studies have highlighted that adjuvants co-administered with antibiotics reduce the oxidative stress, which in turn reduce inflammation [76, 77]. Dwivedi et al.  reported that AAE used for 21 days, the levels of antioxidant enzymes (superoxidase dismutase, catalase, glutathione reductase, glutathione peroxidase), along with xanthine oxidase, lipid peroxidation, myeloperoxidase (MPO) levels, hepatic, and renal parameters were significantly improved in plasma and tissues of the AAE-treated group indicating antioxidant or free radical scavenging properties .
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